Cardiometabolic diseases such as type 2 diabetes (T2DM) and cardiovascular disease (CVD) are common global health conditions that carry a great public health burden for chronic disability and early death. African Americans are more likely to be disproportionately affected than Whites. Our proposed project will have an important impact because it has great potential to explain, 1) A measure of the genetic susceptibility of these cardiometabolic diseases and mortality, and 2) Interaction and mediation of a genetic risk score (GRS) with a low diet quality score and low physical activity levels on these adverse health outcomes. There are published reports of interaction (effect modification) but not mediation (indirectly through an intervening variable) of a GRS with nutritional factors and low physical activity levels on cardiometabolic conditions; however, these studies involving interaction were performed predominantly in Whites. Most of the genetic susceptibility for these outcomes remains unexplained for African Americans. Studies are lacking on the role of these lifestyle factors in terms of interaction and especially mediation with a GRS to increase risk for cardiometabolic outcomes among Whites and African Americans. Thus, several questions remain regarding the influence environmental factors have with genes to increase disease risk and mortality among different race/ethnic groups. To address our questions, we will use the National Heart, Lung and Blood Institute Candidate Gene Association Resource dataset of about 50,000 subjects, including 13,000 African Americans. To account for a measure of the genetic susceptibility, we will capture multiplicative single nucleotide polymorphism effects by the re-weighted random forest statistical method to compute a disease-and-race-specific GRS. We will include functional reduction- oxidation and metabolic disruptive single nucleotide polymorphisms that are involved in the inflammation and nutrient-signaling pathways. We will then investigate interaction and mediation of a GRS with a low diet quality score and low physical activity levels on T2DM, CVD, and mortality at baseline and over time by performing a meta-analysis. Our data include information on genetic polymorphisms, cross-sectional and longitudinal measurements on phenotypes for T2DM, CVD, and mortality, as well as dietary intake, physical activity, and relevant covariates.